An estimated 51,540 new oropharyngeal cancer cases and 10,030 deaths will occur in U.S. during 2018. Oral squamous cell carcinoma (OSCC) is one of the most challenging to treat human cancers due to the insidious nature of its early disease, dependence on radical surgery for treatment and difficulty achieving locoregional control. Further, even OSCC patients who are cured by surgery must face major esthetic and functional changes of their face and mouth. OSCC arises from malignant transformation of its precursor lesion i.e. oral intraepithelial neoplasia (OIN). While not all OINs progress to OSCC, up to 87% of high-risk lesions transform. Despite refined predictive parameters, we do not yet have the methodology to predict which OIN lesions will progress to OSCC. Further, approximately a third of OIN lesions recur despite microscopically clear surgical margins; findings which imply heritable defects in the keratinocyte stem cell pool. As OSCC's devastating effects are well-recognized, numerous OSCC prevention trials have been conducted. The majority of these studies employed systemic delivery and were largely ineffective. Systemic delivery limitations include drug inactivation during first pass metabolism in the liver which results in difficulty achieving therapeutic levels of active drug at the target site and adverse side effects. In contrast, local delivery formulations provide therapeutic levels directly to the treatment site using appreciably less drug and without adverse side effects. The mouth's visible accessibility facilitates agent placement by patients and clinical monitoring. Our lab has previously conducted a local delivery OSCC chemoprevention trial and obtained strong results including complete OIN resolution in some patients. Not all patients derived chemopreventive benefits which prompted development of a new local delivery formulation. The Specific Aims of this proposal are: 1) identify the clinical lead patch formulation in vivo and characterize the metabolic profile of locally delivered fenretinide (4-HPR), 2) confirm application time in healthy participants then evaluate chemopreventive efficacy in persons with microscopically confirmed OIN lesions. Experimental methodology will include PK analyses, LC-MS, IHC and laser capture microdissection followed by LOH analyses. The trial biomarkers (histologic grade, clinical presentation and LOH events) are all associated with OIN progression. This formulation i.e. a 4-HPR patch is expected to provide more pervasive chemopreventive effects across the trial cohort. Public Heath Relevance: Oral cancer, which arises from the cells lining the inside of the mouth, is a devastating cancer that is managed by aggressive surgery. Even if cured by surgery, patients live with swallowing, eating, talking difficulties and deformities to their face and mouth. Previous oral cancer prevention programs, which used pills that could affect the entire body, were not successful and often caused adverse side effects including very sore mouths and night blindness. In contrast, this project introduces a more efficient and safer approach i.e. application of the cancer preventing agent directly to the precancerous tissue.